Continuous epileptiform discharges are associated with worse neurodevelopmental findings in a congenital Zika syndrome prospective cohort.

PURPOSE: This study aimed to identify continuous epileptiform discharges (CEDs) on electroencephalograms (EEG) and to determine their clinical significance in children with congenital Zika syndrome (CZS). METHODS: This prospective cohort study included 75 children diagnosed with CZS born from March 2015 and followed up until September 2018 (age up to 36 months). EEG was performed to detect CEDs up to 24 months old. Data on obstetric, demographic, and clinical signs; cranial computed tomography (CT); ophthalmology examination; anti-seizure medication; growth; and motor development were collected. Fisher's exact test was used to verify the associations between categorical variables, and the T- test was used to compare the mean z-scores of anthropometric measurements between the groups with and without CED. RESULTS: CEDs were identified in 41 (54.67 %) children. The mean age of CEDs identification was 12.24 ± 6.86 months. Bilateral CEDs were shown in 62.89 % of EEGs. CEDs were associated with severe congenital microcephaly, defined by z-score >3 standard deviation of head circumference (HC) below the mean for sex and age (p = 0.025), and worse outcomes, including first seizure before 6 months (p = 0.004), drug-resistant epilepsy (p < 0.001), chorioretinal scarring or mottling (p = 0.002), and severe CT findings (p = 0.002). The CED group had lower mean z-scores of HC up to 24 months of age. CONCLUSION: This is the first description of the prevalence and significance of CEDs that also remains during wakefulness in patients with CZS. New investigations may suggest that it is more appropriate to classify the EEG not as a CED, but as a periodic pattern. Anyway, CEDs may be a marker of neurological severity in children with CSZ.

Characteristics associated with drug resistant epilepsy in children up to 36 months old with Congenital Zika Syndrome.

OBJECTIVES: To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS). METHODS: This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected. RESULTS: Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months. CONCLUSIONS: The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum.

Decline in head circumference growth and associated factors in congenital Zika syndrome.

Little is known about the evolution of head circumference (HC) in children with congenital Zika syndrome (CZS). This study aims to evaluate HC growth in children with CZS in the first three years of life and identify associated factors. HC data obtained at birth and in neuropediatric consultations from 74 children with CZS were collected from the Child's Health Handbook, parents' reports, and medical records. Predictors of HC z-score were investigated using different mixed-effects models; Akaike's information criterion was used for model selection. The HC z-score decreased from -2.7 ± 1.6 at birth to -5.5 ± 2.2 at 3 months of age, remaining relatively stable thereafter. In the selected adjusted model, the presence of severe brain parenchymal atrophy and maternal symptoms of infection in the first trimester of pregnancy were associated with a more pronounced reduction in the HC z-score in the first three years of life. The decrease of HC z-score in CZS children over the first three months demonstrated a reduced potential for growth and development of the central nervous system of these children. The prognosis of head growth in the first 3 years of life is worse when maternal infection occurs in the first gestational trimester and in children who have severe brain parenchymal atrophy.

Decline in head circumference growth and associated factors in congenital Zika syndrome / Declínio no crescimento do perímetro cefálico e fatores associados à síndrome congênita associada à infecção pelo vírus Zika / Disminución del crecimiento del perímetro cefálico y factores asociados en el síndrome congénito del Zika

Little is known about the evolution of head circumference (HC) in children with congenital Zika syndrome (CZS). This study aims to evaluate HC growth in children with CZS in the first three years of life and identify associated factors. HC data obtained at birth and in neuropediatric consultations from 74 children with CZS were collected from the Child's Health Handbook, parents' reports, and medical records. Predictors of HC z-score were investigated using different mixed-effects models; Akaike's information criterion was used for model selection. The HC z-score decreased from -2.7 ± 1.6 at birth to -5.5 ± 2.2 at 3 months of age, remaining relatively stable thereafter. In the selected adjusted model, the presence of severe brain parenchymal atrophy and maternal symptoms of infection in the first trimester of pregnancy were associated with a more pronounced reduction in the HC z-score in the first three years of life. The decrease of HC z-score in CZS children over the first three months demonstrated a reduced potential for growth and development of the central nervous system of these children. The prognosis of head growth in the first 3 years of life is worse when maternal infection occurs in the first gestational trimester and in children who have severe brain parenchymal atrophy.

Pouco se sabe sobre a evolução do perímetro cefálico (PC) em crianças com síndrome congênita associada à infecção pelo vírus Zika (SCZ) em acompanhamentos contínuos. Este estudo buscou avaliar o crescimento do PC em crianças com SCZ nos primeiros três anos de suas vidas e identificar os fatores associados a ele. Os dados do PC ao nascimento e obtidos em consultas neuropediátricas de 74 crianças com SCZ foram coletados no Cartão da Criança, nos laudos paternos e em seus prontuários. Os preditores de escore-z para PC foram investigados utilizando-se diferentes modelos de efeitos mistos. O critério de informação de Akaike foi utilizado para selecionar os modelos usados. O escore-z de PC diminuiu de -2,7 ± 1,6 ao nascimento para -5,5 ± 2,2 aos 3 meses de idade, mas permaneceu relativamente estável desde então. No modelo ajustado selecionado, a presença de atrofia parênquimal cerebral grave e sintomas maternos de infecção no primeiro trimestre de sua gravidez estiveram associados a uma redução mais acentuada no escore-z de PC nos primeiros três anos de vida dos participantes. A diminuição do escore-z de PC em crianças com SCZ nos primeiros 3 meses de sua vida monstra o potencial reduzido de crescimento e desenvolvimento do sistema nervoso central dessas crianças. O prognóstico de crescimento do perímetro cefálico nos primeiros 3 anos de vida é pior quando a infecção materna ocorreu no primeiro trimestre gestacional e em crianças que tiveram atrofia parênquimal grave.

Se conoce poco sobre la evolución del perímetro cefálico (PC) en niños con síndrome de Zika congénito (SZC) en los seguimientos continuos. El objetivo del estudio fue evaluar el crecimiento del PC en niños con SZC en los primeros 3 años de vida e identificar los factores asociados. Se recogieron datos del PC al nacimiento y obtenidos en las consultas de neuropediatría de 74 niños con SZC a partir de la Tarjeta del Niño, los informes de los padres y los registros médicos. Se investigaron los predictores de la puntuación Z del PC mediante diferentes modelos de efectos mixtos; se utilizó el criterio de información de Akaike para la selección del modelo. La puntuación Z del PC disminuyó de -2,7 ± 1,6 al nacer a -5,5 ± 2,2 a los 3 meses de edad, pero a partir de entonces se mantuvo relativamente estable. En el modelo ajustado seleccionado, la presencia de atrofia grave del parénquima cerebral y los síntomas maternos de infección en el primer trimestre del embarazo se asociaron con una reducción más pronunciada de la puntuación Z del PC en los primeros 3 años de vida. La disminución de la puntuación Z del PC en los niños con SZC durante los primeros 3 meses demuestra el menor potencial de crecimiento y desarrollo del sistema nervioso central de estos niños. El pronóstico del crecimiento de la cabeza en los primeros 3 años de vida es peor cuando la infección materna se produjo en el primer trimestre gestacional y en los niños que tenían una atrofia grave del parénquima cerebral.

Congenital Zika syndrome: Growth, clinical, and motor development outcomes up to 36 months of age and differences according to microcephaly at birth.

BACKGROUND: Little is known regarding the developmental consequences of congenital Zika syndrome (CZS) without microcephaly at birth. Most previously published clinical series were descriptive and they had small sample sizes. STUDY DESIGN: We conducted a cohort study to compare the growth, clinical, and motor development outcomes for 110 children with CZS born with and without microcephaly up to their third birthday. Ninety-three had their head circumference (HC) at birth abstracted and they did not have hypertensive hydrocephalus at birth, where 61 were born with microcephaly and 32 without. RESULTS: The HC z-scores decreased steeply from birth to six months of age, i.e., from -3.77 to -6.39 among those with microcephaly at birth and from -1.03 to -3.84 among those without. Thus, at 6 months of age, the mean HC z-scores for children born without microcephaly were nearly the same as those for children born with microcephaly. Children born without microcephaly were less likely to have brain damage, ophthalmic abnormalities, and drug-resistant epilepsy, but the differences in many conditions were not statistically significant. CONCLUSIONS: Children born without microcephaly were only slightly less likely to present severe neurologic impairment and to develop postnatal-onset microcephaly, and some of the original differences between the groups tended to dissipate with age.

Gross Motor Function in Children with Congenital Zika Syndrome.

BACKGROUND: Little information on gross motor function of congenital Zika syndrome (CZS) children is available. OBJECTIVES: To evaluate gross motor function in CZS children aged up to 3 years, and its associated factors and changes in a minimum interval of 6 months. METHODS: One hundred children with CZS and cerebral palsy (36 with confirmed and 64 with presumed CZS) were evaluated with the Gross Motor Function Classification System (GMFCS) and Gross Motor Function Measure (GMFM-88/GMFM-66). Forty-six were reevaluated. Wilcoxon tests, Wilcoxon tests for paired samples, percentile scores, and score changes were performed. RESULTS: Clinical and socioeconomic characteristics (except maternal age), GMFM scores and GMFCS classification of confirmed and probable cases, which were analyzed together, were similar. The mean age was 25.6 months (±5.5); the median GMFM-88 score was 8.0 (5.4-10.8); and the median GMFM-66 score was 20.5 (14.8-23.1); 89% were classified as GMFCS level V. Low economic class, microcephaly at birth, epilepsy, and brain parenchymal volume loss were associated with low GMFM-66 scores. The median GMFM-66 percentile score was 40 (20-55). On the second assessment, the GMFM-66 scores in two GMFCS level I children and one GMFCS level IV child improved significantly. In one GMFCS level III child, one GMFCS level IV child, and the group of GMFCS level V children, no significant changes were observed. CONCLUSIONS: Almost all CZS children had severe cerebral palsy; in the third year of life, most presented no improvement in gross motor function and were likely approaching their maximal gross motor function potential.

Congenital Zika syndrome: association between the gestational trimester of maternal infection, severity of brain computed tomography findings and microcephaly at birth.

This study analyzed possible associations between the trimester of maternal Zika virus infection (ZIKV) in pregnancy, severity of brain computed tomography (CT) findings and the presence of microcephaly at birth in children with Congenital Zika Syndrome (CZS). It was an analytical study in a cohort of children with CZS. Symptoms of maternal infection were dichotomized into the 1st trimester of pregnancy and other trimesters. Head circumference (HC) at birth was used to calculate the z-score. Mild microcephaly was defined as HC between 2 and ≥3 standard deviations (SD) below the mean for each gestational age and sex, and severe microcephaly when HC <3 SD below average. Brain CT images were evaluated by two radiologists and classified, according to the severity, into mild, moderate and severe. Fisher's exact, Mann-Whitney and Kruskal-Wallis tests were used to verify the associations between variables. In 108 children, maternal infection in the 1st trimester of pregnancy was associated with more severe brain CT abnormalities (p=0.038), greater severity of microcephaly at birth (p=0.013) and lower HC z-scores at birth (p=0.021). The severity of brain CT lesions was also associated with lower HC z-scores at birth (p<0.001). Maternal ZIKV infection during the first trimester of pregnancy proved to be an important risk factor for a more severe spectrum of CZS, as it is associated with more severe brain CT abnormalities and, consequently, with lower HC z-scores at birth.